巨噬细胞与纤维环细胞交互作用中PDGF-C/PDGFR-α导致椎间盘退变的机制研究

In recent years a number of researches show that comparatively close relationship between PDGF/PDGFR signaling pathway and the fibrosis of a lot of tissues and organs. However, different PDGF ligands in the occurrence and development of fibrosis have different functions. Annulus fibrosus cell degeneration and artilaginous metaplasia are the pathological basis of intervertebral disc degeneration. And effects of PDGFs/PDGFRs signaling pathway in micro-environment of inflammation for intervertebral disc degeneration and fibrosis process is still unknown. In our previous study, we found that higher expressions of PDGF-C and its receptor PDGFR in the intervertebral disc degeneration than control, suggesting that it plays an important function in the progression of the pathological process. Based on the research hotspot of lumbar intervertebral disc degeneration and pathological microenvironment, combined with our latest research results, this project tries to explore PDGF-C/PDGFR-α signaling pathway for the interaction between macrophages in inflammation and annulus fibrosus cells, and the molecular mechanism of lumbar intervertebral disc degeneration and fibrosis process. And inhibiting the inflammatory reaction or PDGF-C/PDGFR-αsignal pathway via aspirin or imatinib respectively, we want to clarify the effectiveness and mechanism on reducing the degree of disc degeneration and delaying the process of fibrosis.

近年来大量研究表明PDGF/PDGFR信号通路与多种组织器官的纤维化之间关系较为密切，然而不同的PDGF配体所驱动的功能在纤维化发生发展过程中各有不同。纤维环细胞的退变、软骨化生是椎间盘退变的病理基础，而有关炎症微环境PDGFs/PDGFRs信号通路异常调控在椎间盘退行性纤维化过程中作用的研究尚属空白。我们前期研究发现PDGF-C及其受体PDGFR-α在椎间盘退变中大量表达，提示其在该疾病过程进展中发挥重要功能。本项目围绕腰椎间盘退变和病理微环境研究热点，结合项目组最新研究成果，探讨PDGF-C/PDGFR-α信号通路介导的椎间盘炎症巨噬细胞与纤维环细胞相互影响和调控作用的分子机制，探讨该信号的异常调控在腰椎间盘退行性病变过程及纤维化过程中的作用。并进一步分析应用阿司匹林或伊马替尼，分别阻断炎症反应或 PDGF-C/PDGFR-α信号通路，能否有效减轻椎间盘退变程度及延缓纤维化过程。

近年来大量研究表明PDGF/PDGFR信号通路与多种组织器官的纤维化之间关系较为密切，然而不同的PDGF配体所驱动的功能在纤维化发生发展过程中各有不同。同时，炎症反应也在椎间盘退变中扮演着重要角色。我们的前期研究发现PDGF-CC及其受体PDGFR-α在椎间盘退变中大量表达，且巨噬细胞在退变的椎间盘中广泛浸润。以上提示两者在该疾病过程进展中发挥重要功能。本项目围绕椎间盘退变和病理微环境这一热点，结合我们最新研究成果后，揭示了PDGF-CC/PDGF-α信号通路介导的椎间盘退变过程中巨噬细胞的浸润和极性转化，及巨噬细胞与髓核细胞之间相互影响和调控作用的分子机制。最后，本项目探讨了早期应用外源性PDGF-CC用于延缓椎间盘退变的可能性。目前国内外尚无关于PDGF-CC/PDGF-α与巨噬细胞极化、椎间盘退变之间关系的相关研究。本研究的完成将有助于阐明巨噬细胞中PDGF-CC/PDGF-α信号通路的异常调控在椎间盘退变中发挥的重要功能，了解疾病微环境中炎症细胞与病变组织细胞相互诱导和调控机制，为椎间盘退行性疾病的防治奠定坚实可靠的理论基础和实验保证。